CB1 Cannabinoid Receptor Activation Rescues Amyloid ß-Induced Alterations in Behaviour and Intrinsic Electrophysiological Properties of Rat Hippocampal CA1 Pyramidal Neurones

Abstract

Background: Amyloid beta (Aβ) is believed to be responsible for the synaptic failure that occurs in Alzheimer′s disease (AD), but there is little known about the functional impact of Aβ on intrinsic neuronal properties. Here, the cellular effect of Aβ-induced neurotoxicity on the electrophysiological properties of CA1 pyramidal neurons and the mechanism(s) of neuroprotection by CB1 cannabinoid receptor activation was explored. Methods: A combination of behavioural, molecular and electrophysiological approaches was used. Results: Bilateral injections of the Aβ peptide fragment (1-42) into the prefrontal cortex caused a significant impairment in the retention and recall capability in the passive avoidance tasks and significantly increased the level of active caspase-3 in the hippocampus. Whole-cell patch clamp recordings revealed a significant reduction in the intrinsic action potential (AP) frequency and an increase in the discharge irregularity in the absence of synaptic inputs in Aβ treated group. Aβ treatment induced also significant changes in both the spontaneous and evoked neuronal responses. However, co-treatment with ACEA, a CB1 receptor agonist, preserved almost the normal intrinsic electrophysiological properties of pyramidal cells. Conclusions: In vivo Aβ treatment altered significantly the intrinsic electrophysiological properties of CA1 pyramidal neurons and the activation of CB1 cannabinoid receptors exerted a strong neuroprotective action against Aβ toxicity.

β-Amyloid Inhibits E-S Potentiation through Suppression of Cannabinoid Receptor 1-Dependent Synaptic Disinhibition

“…The mechanism by which Aβ disables the effects of cannabinoids on synaptic inhibition, and thus disrupts plasticity, may explain learning and memory deficits in AD that occur in otherwise healthy neural circuits prior to AD-related neuronal cell death. Changes in neuronal circuitry of the hippocampus have been reported long before appearance of the signal sign of Alzheimer's disease, amyloid plaques (Hsia et al, 1999), and impaired cannabinoid signaling may play a role in that aspect of the neuropathology (Aso et al, 2012; Gowran et al, 2011; Haghani et al, 2012a; Haghani et al, 2012b; Stumm et al, 2013). The present discovery of an explicit role for Aβ in suppressing cannabinoid function elucidates a substrate of Alzheimer's pathology.…”

Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic

“…Similar positive results in the survival of neuronal cultures exposed to Aβ peptide were obtained with exogenous cannabinoids such as CBD (Iuvone et al, 2004; Janefjord et al, 2013), the selective CB 1 receptor agonist arachidonyl-2-chloroethylamide (ACEA; Aso et al, 2012), the CB 2 selective agonists JWH-015 and JWH-133, and the mixed CB 1 /CB 2 receptor agonists Δ 9 -THC, HU-210, and WIN55,212-2 (Ramírez et al, 2005; Janefjord et al, 2013). The neuroprotective properties of exogenous cannabinoids have consistently been demonstrated to prevent memory deficits in Aβ-injected rats and mice for both synthetic CB 1 (Haghani et al, 2012) and CB 2 selective agonists (Wu et al, 2013), as well as mixed CB 1 /CB 2 receptor agonists (Ramírez et al, 2005; Martín-Moreno et al, 2011; Fakhfouri et al, 2012) and natural CBD (Martín-Moreno et al, 2011). Moreover, chronic treatment with ACEA (Aso et al, 2012), JWH-133 (Martín-Moreno et al, 2012; Aso et al, 2013), or WIN55,212-2 (Martín-Moreno et al, 2012) resulted in cognitive improvement in two different transgenic mouse models of brain amyloidosis.…”

Pharmacological blockade of TRPV1 receptors modulates the effects of 6‐OHDA on motor and cognitive functions in a rat model of Parkinson's disease

“…The maximum cutoff time for the step-through latency was 300 s when the rat did not enter the dark chamber in the retention trials [19]. The rats were allowed to step into the dark compartment, and then the latency to re-enter the dark chamber was recorded.…”